Center for Molecular Medicine Cologne

Miguel A Alejandre Alcazar | Manuel Koch - C 01

Netrin-1 as a new target to treat chronic lung disease: Identification of agonists and antagonists by artificial intelligence

Introduction

Bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease, is characterised by inflammation, matrix remodeling and lung growth arrest. The lack of therapies emphasizes the need to define new therapeutic strategies to prevent acute injury and promote lung regeneration. Since netrin-1 has anti-inflammatory and stemness-promoting function, we aim to identify novel netrin-1 targeting agonists and antagonists to promote alveolarization by preventing inflammation and matrix remodeling in neonatal chronic lung disease.

Preterm infants, whose lungs are incompletely developed, are at high risk for respiratory failure. Oxygen (O2) and mechanical ventilation (MV) offer life-saving treatments for respiratory distress; such treatment, however, leads to bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Despite the advances in perinatal care, BPD is the most common complication of prematurity. Lungs of infants afflicted with BPD are characterized by impaired formation of alveoli and pulmonary micro-vessels as well as perturbed matrix remodeling, yielding structural changes resembling emphysema or chronic obstructive lung disease (COPD).

These structural and functional sequelae of prematurity persist beyond infancy, suggesting a reduced regenerative capacity of lungs with BPD. Inflammation and perturbed matrix remodeling favoring fibrosis are intimately linked to the pathogenesis of BPD. The high incidence of BPD and the lack of pharmaceutical therapies emphasize the need of unravelling the early molecular origins that cause the initial lung injury to identify novel targets in BPD to inhibit inflammation, to preserve lung matrix and thereby lung growth. 

Molecular mechanisms of experimental and clinical BPD

The pathogenesis of BPD includes inflammation, matrix remodeling and reduced regeneration, but the mechanisms are not yet known. Our research group has established two animal models of neonatal lung growth arrest, hyperoxia- and ventilation-induced lung injury. Neonatal lung growth arrest was related to an infiltration of immune cells in the lung, to increased protease activity and elevated inflammatory cytokines, e.g. IL6.  Moreover, we found that Krüppel-like factor 4 (Klf4), a zinc-finger transcription factor that plays a major role in regulating cell pluripotency, cell survival and cell differentiation as well as inflammation, is markedly reduced in neonatal lungs with growth arrest.

We studied the role of Klf4 in vivo and in vitro and identified Klf4 as a key regulator of alveolar epithelial cells type II (ATII), the alveolar progenitor cells that promote alveolar regeneration. Our translational studies showed that ATII-specific ablation of Klf4 during alveolarization promotes ATII differentiation and enables lung growth. These findings highlight Klf4 as a novel target to promote lung growth and regeneration.

Blocking inflammation to enable lung growth

The pathogenesis of BPD includes inflammation, but the mechanisms are not yet known. Macrophages are key constituents of lung inflammation, secreting various cytokines, such as Interleukin 6 (IL6), CXCL10 and MMP12, regulator of cell homeostasis, matrix remodeling, immune response and tissue regeneration.Interestingly,Klf4 has been identified as a key regulator of macrophage differentiation, maintaining anti-inflammatory M2 phenotype; in contrast, deletion of Klf4 favors inflammatory M1. Infants evolving BPD, show an elevation of M1 markers, whereas M2 markers are unchanged or even reduced.

Similarly, in models of neonatal lung growth arrest a macrophage influx is linked to increased protease activity and macrophage-related cytokines, e.g. IL6. We next tested if blockade of these cytokines enables lung formation after hyperoxia. Indeed, IL6 and MMP12 null mice were partly protected from hyperoxia-induced lung injury. In particular, loss of IL6 preserved survival and homeostasis of ATII, alveolar formation, and ultimately lung function, suggesting IL6 as a novel therapeutical target to treat BPD.

Our Aims

BPD remains a devastating disease of extreme premature infants. Our future perspective aims to target Klf4 in three major pathomechanisms of BPD: (1) regenerative capacity; (2) matrix remodelling; and (3) inflammation. Effective treatment or prevention of hyperoxia- or ventilator-induced lung injury evolving into BPD likely will derive from elucidating molecular mechanisms causing initial injury, which is the central goal of our research group.

  • Dinger K, Koningsbruggen-Rietschel SV, Dotsch J, and Alejandre Alcazar MA (2020). Identification of Critical Windows of Metabolic Programming of Metabolism and Lung Function in Male Offspring of Obese Dams. Clinical and translational science 10.1111/cts.12811.
     
  • Korner RW, Majjouti M, Alcazar MAA, and Mahabir E (2020). Of Mice and Men: The Coronavirus MHV and Mouse Models as a Translational Approach to Understand SARS-CoV-2. Viruses 12.
     
  • Kuiper-Makris C, Zanetti D, Vohlen C, Fahle L, Muller M, Odenthal M, Felderhoff-Muser U, Dotsch J, and Alejandre Alcazar MA (2020). Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function. Sci Rep 10, 22395.
     
  • Litzenburger T, Huber EK, Dinger K, Wilke R, Vohlen C, Selle J, Kadah M, Persigehl T, Heneweer C, Dotsch J, and Alcazar MAA (2020). Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in he offspring. Clin Sci 134, 921-39.
     
  • Polanyi L, Niessen CM, Vohlen C, Stinn J, Kretschmer T, Jentgen V, Hirani D, Koningsbruggen-Rietschel SV, Dotsch J, and Alejandre Alcazar MA (2020). Intrauterine growth restriction induces skin inflammation, increases TSLP and impairs epidermal barrier function. J Mol Med (Berl) 98, 279-89.
     
  • Wagner DE, Ubags ND, Troosters T, and Alejandre Alcazar MA (2020). Fostering the integration of basic respiratory science and translational pulmonary medicine for the future. American journal of physiology Lung cellular and molecular physiology 319, L538-L40.
     
  • Imhof T, Korkmaz Y, Koch M, Sengle G, and Schiavinato A (2020a). EMILIN proteins are novel extracellular constituents of the dentin-pulp complex. Sci Rep 10, 15320.
     
  • Imhof T, Rosenblatt K, Pryymachuk G, Weiland D, Noetzel N, Deschner J, Baris OR, Kimoloi S, Koch M, Wiesner RJ, and Korkmaz Y (2020b). Epithelial loss of mitochondrial oxidative phosphorylation leads to disturbed enamel and impaired dentin matrix formation in postnatal developed mouse incisor. Sci Rep 10, 22037.
     
  • Izu Y, Adams SM, Connizzo BK, Beason DP, Soslowsky LJ, Koch M, and Birk DE (2020). Collagen XII mediated cellular and extracellular mechanisms regulate establishment of tendon structure and function. Matrix Biol 10.1016/j.matbio.2020.10.004.
     
  • Koch M, Reinartz S, Saggau J, Knittel G, Rosen N, Fedorchenko O, Thelen L, Barthel R, Reinart N, Seeger-Nukpezah T, Reinhardt HC, Hallek M, and Nguyen PH (2020). Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Emicro-TCL1 Transgenic Mouse Model. Cancers (Basel) 12.
     
  • Kohler A, Morgelin M, Gebauer JM, Ocal S, Imhof T, Koch M, Nagata K, Paulsson M, Zaucke F, Baumann U, and Sengle G (2020). New specific HSP47 functions in collagen subfamily chaperoning. FASEB J 10.1096/fj.202000570R.
     
  • Kreer C, Zehner M, Weber T, Ercanoglu MS, Gieselmann L, Rohde C, Halwe S, Korenkov M, Schommers P, Vanshylla K, Di Cristanziano V, Janicki H, Brinker R, Ashurov A, Krahling V, Kupke A, Cohen-Dvashi H, Koch M, Eckert JM, Lederer S, Pfeifer N, Wolf T, Vehreschild MJGT, Wendtner C, Diskin R, Gruell H, Becker S, and Klein F (2020c). Longitudinal Isolation of Potent Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients. Cell 182, 843-+.
     
  • Matin M, Morgelin M, Stetefeld J, Schermer B, Brinkkoetter PT, Benzing T, Koch M, and Hagmann H (2020). Affinity-Enhanced Multimeric VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) Variants for Specific Adsorption of sFlt-1 to Restore Angiogenic Balance in Preeclampsia. Hypertension 76, 1176-84.
     
  • Salabarria AC, Koch M, Schonberg A, Zinser E, Hos D, Hamdorf M, Imhof T, Braun G, Cursiefen C, and Bock F (2020). Topical VEGF-C/D Inhibition Prevents Lymphatic Vessel Ingrowth into Cornea but Does Not Improve Corneal Graft Survival. J Clin Med 9.
     
  • Schermer B, Fabretti F, Damagnez M, Di Cristanziano V, Heger E, Arjune S, Tanner NA, Imhof T, Koch M, Ladha A, Joung J, Gootenberg JS, Abudayyeh OO, Burst V, Zhang F, Klein F, Benzing T, and Muller RU (2020). Rapid SARS-CoV-2 testing in primary material based on a novel multiplex RT-LAMP assay. PloS one 15, e0238612.
Prof. Dr. Dr. Miguel A Alejandre Alcazar CMMC Cologne
Prof. Dr. Dr. Miguel A Alejandre Alcazar

Clinic and Polyclinic for Pediatric and Adolescent Medicine

Principal Investigator - C 01 | CAP 10

+49 221 478 96876

+49 221 478 32400

Clinic and Polyclinic for Pediatric and Adolescent Medicine

Kerpener Str. 62

50937 Cologne

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Prof. Dr. Manuel Koch CMMC Cologne
Prof. Dr. Manuel Koch

Institute for Dental Research and Musculoskeletal Biology

Co - Principal Investigator - C 01

Institute for Dental Research and Musculoskeletal Biology

c/o Institut für Biochemie II Joseph-Stelzmann-Str. 52

50931 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Manuel Koch

Link to PubMed

Group Members

Serife Akgül
Janina Betz
Thomas Imhof
Dharmesh Hirani
Jasmine Mohr
Fabian Metzen
Jaco Selle